PROJECT SUMMARY Underactive bladder (UAB) is a clinically important problem in the elderly. UAB is characterized by weak bladder contractions and incomplete bladder emptying that result in symptoms of voiding frequency, nocturia, and incontinence, and it can lead to serious complications such as permanent bladder and kidney damage. Aging-related UAB may affect almost 25% of Americans over 60, and nearly two-thirds of incontinent nursing home residents exhibit UAB. Globally, increased life expectancy is expected to increase the number of patients with UAB and lower urinary tract symptoms. The current standard treatment to achieve complete bladder emptying in UAB patients is intermittent catheterization. Although drug therapies are sometimes used to manage milder forms of UAB, those currently available have poor efficacy and tolerability and may not be suitable for use in elderly patients due to multiple side effects. A safe and effective product that facilitates efficient, complete voiding would provide a paradigm shift in the management of UAB. Dignify Therapeutics is developing next-generation potent and selective NK2R agonists to produce on-demand voiding as a treatment for UAB. Drug-induced side effects such as hypotension are a particular concern in the elderly as they can lead to mental confusion, poor mobility, and debilitating falls. Thus, a selective, short duration NK2R agonist would be desirable for use in this population. In Phase I, two next-generation NK2R agonists were identified that have optimized selectivity, improved pharmacokinetic (PK) profiles, and improved therapeutic indices. In this Phase II project, prototype formulations for convenient administration several times a day will be developed and tested for efficacy and improved side effect profiles in adult and aged preclinical animal models. Prototype intranasal (IN) and orally disintegrating tablet (ODT) formulations of optimized NK2R agonists will be developed and manufactured for preclinical studies. Qualified bioanalytical methods for plasma detection will also be developed. The therapeutic index, pharmacodynamic (PD), and PK profiles will be characterized following acute and repeated long-term IN dosing in aged rats and optimized ODT and IN formulations will be characterized in anesthetized and awake dogs. The proposed Phase II project will allow Dignify Therapeutics to develop an optimized ?on-demand, rapid-onset, short-duration, drug-induced, voiding therapy? to treat UAB in the elderly. This optimized therapy will reduce the risk of deleterious side effects by providing greater target selectivity and a reduced duration of action. This therapy would greatly improve the daily routine of elderly individuals with UAB, reduce UTIs and associated health risks, and decrease overall healthcare costs.